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BMC Veterinary Research May 2024Hypoxia is a detrimental factor in solid tumors, leading to aggressiveness and therapy resistance. OMX, a tunable oxygen carrier from the heme nitric...
BACKGROUND
Hypoxia is a detrimental factor in solid tumors, leading to aggressiveness and therapy resistance. OMX, a tunable oxygen carrier from the heme nitric oxide/oxygen-binding (H-NOX) protein family, has the potential to reduce tumor hypoxia. [F]Fluoromisonidazole ([F]FMISO) positron emission tomography (PET) is the most widely used and investigated method for non-invasive imaging of tumor hypoxia. In this study, we used [F]FMISO PET/CT (computed tomography) to assess the effect of OMX on tumor hypoxia in spontaneous canine tumors.
RESULTS
Thirteen canine patients with various tumors (n = 14) were randomly divided into blocks of two, with the treatment groups alternating between receiving intratumoral (IT) OMX injection (OMX IT group) and intravenous (IV) OMX injection (OMX IV group). Tumors were regarded as hypoxic if maximum tumor-to-muscle ratio (TMR) was greater than 1.4. In addition, hypoxic volume (HV) was defined as the region with tumor-to-muscle ratio greater than 1.4 on [F]FMISO PET images. Hypoxia was detected in 6/7 tumors in the OMX IT group and 5/7 tumors in the OMX IV injection group. Although there was no significant difference in baseline hypoxia between the OMX IT and IV groups, the two groups showed different responses to OMX. In the OMX IV group, hypoxic tumors (n = 5) exhibited significant reductions in tumor hypoxia, as indicated by decreased TMR and HV in [F]FMISO PET imaging after treatment. In contrast, hypoxic tumors in the OMX IT group (n = 6) displayed a significant increase in [F]FMISO uptake and variable changes in TMR and HV.
CONCLUSIONS
[F]FMISO PET/CT imaging presents a promising non-invasive procedure for monitoring tumor hypoxia and assessing the efficacy of hypoxia-modulating therapies in canine patients. OMX has shown promising outcomes in reducing tumor hypoxia, especially when administered intravenously, as evident from reductions in both TMR and HV in [F]FMISO PET imaging.
Topics: Animals; Dogs; Misonidazole; Positron Emission Tomography Computed Tomography; Dog Diseases; Female; Tumor Hypoxia; Male; Neoplasms; Thiosemicarbazones; Coordination Complexes
PubMed: 38741109
DOI: 10.1186/s12917-024-04061-4 -
BioMed Research International 2024Glioblastoma is the most aggressive primary brain tumor, characterized by its distinctive intratumoral hypoxia. Sequential preoperative examinations using...
Identifying G6PC3 as a Potential Key Molecule in Hypoxic Glucose Metabolism of Glioblastoma Derived from the Depiction of F-Fluoromisonidazole and F-Fluorodeoxyglucose Positron Emission Tomography.
PURPOSE
Glioblastoma is the most aggressive primary brain tumor, characterized by its distinctive intratumoral hypoxia. Sequential preoperative examinations using fluorine-18-fluoromisonidazole (F-FMISO) and fluorine-18-fluorodeoxyglucose (F-FDG) positron emission tomography (PET) could depict the degree of glucose metabolism with hypoxic condition. However, molecular mechanism of glucose metabolism under hypoxia in glioblastoma has been unclear. The aim of this study was to identify the key molecules of hypoxic glucose metabolism.
METHODS
Using surgically obtained specimens, gene expressions associated with glucose metabolism were analyzed in patients with glioblastoma ( = 33) who underwent preoperative F-FMISO and F-FDG PET to identify affected molecules according to hypoxic condition. Tumor metabolic activities were semiquantitatively evaluated by lesion-normal tissue ratio (LNR). Protein expression was confirmed by immunofluorescence staining. To evaluate prognostic value, relationship between gene expression and overall survival was explored in another independent nonoverlapping clinical cohort ( = 17) and validated by The Cancer Genome Atlas (TCGA) database ( = 167).
RESULTS
Among the genes involving glucose metabolic pathway, mRNA expression of () correlated with F-FDG LNR ( = 0.03). In addition, mRNA expression in F-FMISO high-accumulated glioblastomas was significantly higher than that in F-FMISO low-accumulated glioblastomas ( < 0.01). Protein expression of G6PC3 was consistent with mRNA expression, which was confirmed by immunofluorescence analysis. These findings indicated that the G6PC3 expression might be facilitated by hypoxic condition in glioblastomas. Next, we investigated the clinical relevance of in terms of prognosis. Among the glioblastoma patients who received gross total resection, mRNA expressions of in the patients with poor prognosis (less than 1-year survival) were significantly higher than that in the patients who survive more than 3 years. Moreover, high mRNA expression of was associated with poor overall survival in glioblastoma, as validated by TCGA database.
CONCLUSION
G6PC3 was affluently expressed in glioblastoma tissues with coincidentally high F-FDG and F-FMISO accumulation. Further, it might work as a prognostic biomarker of glioblastoma. Therefore, G6PC3 is a potential key molecule of glucose metabolism under hypoxia in glioblastoma.
Topics: Humans; Glioblastoma; Fluorodeoxyglucose F18; Tomography, X-Ray Computed; Positron-Emission Tomography; Glucose; Hypoxia; RNA, Messenger; Glucose-6-Phosphatase; Fluorine Radioisotopes; Misonidazole
PubMed: 38449509
DOI: 10.1155/2024/2973407 -
European Journal of Nuclear Medicine... Aug 2023Tumor hypoxia and other microenvironmental factors are key determinants of treatment resistance. Hypoxia positron emission tomography (PET) and functional magnetic...
PURPOSE
Tumor hypoxia and other microenvironmental factors are key determinants of treatment resistance. Hypoxia positron emission tomography (PET) and functional magnetic resonance imaging (MRI) are established prognostic imaging modalities to identify radiation resistance in head-and-neck cancer (HNC). The aim of this preclinical study was to develop a multi-parametric imaging parameter specifically for focal radiotherapy (RT) dose escalation using HNC xenografts of different radiation sensitivities.
METHODS
A total of eight human HNC xenograft models were implanted into 68 immunodeficient mice. Combined PET/MRI using dynamic [18F]-fluoromisonidazole (FMISO) hypoxia PET, diffusion-weighted (DW), and dynamic contrast-enhanced MRI was carried out before and after fractionated RT (10 × 2 Gy). Imaging data were analyzed on voxel-basis using principal component (PC) analysis for dynamic data and apparent diffusion coefficients (ADCs) for DW-MRI. A data- and hypothesis-driven machine learning model was trained to identify clusters of high-risk subvolumes (HRSs) from multi-dimensional (1-5D) pre-clinical imaging data before and after RT. The stratification potential of each 1D to 5D model with respect to radiation sensitivity was evaluated using Cohen's d-score and compared to classical features such as mean/peak/maximum standardized uptake values (SUV) and tumor-to-muscle-ratios (TMR) as well as minimum/valley/maximum/mean ADC.
RESULTS
Complete 5D imaging data were available for 42 animals. The final preclinical model for HRS identification at baseline yielding the highest stratification potential was defined in 3D imaging space based on ADC and two FMISO PCs ([Formula: see text]). In 1D imaging space, only clusters of ADC revealed significant stratification potential ([Formula: see text]). Among all classical features, only ADC showed significant correlation to radiation resistance ([Formula: see text]). After 2 weeks of RT, FMISO_c1 showed significant correlation to radiation resistance ([Formula: see text]).
CONCLUSION
A quantitative imaging metric was described in a preclinical study indicating that radiation-resistant subvolumes in HNC may be detected by clusters of ADC and FMISO using combined PET/MRI which are potential targets for future functional image-guided RT dose-painting approaches and require clinical validation.
Topics: Humans; Animals; Mice; Diffusion Magnetic Resonance Imaging; Positron-Emission Tomography; Misonidazole; Magnetic Resonance Imaging; Head and Neck Neoplasms; Hypoxia; Radiopharmaceuticals
PubMed: 37148296
DOI: 10.1007/s00259-023-06254-9 -
Scientific Reports Dec 2022Positron emission tomography (PET)/computed tomography (CT) using the radiotracer 18F-Fluoromisonidazole (FMISO) has been widely employed to image tumour hypoxia and is...
Positron emission tomography (PET)/computed tomography (CT) using the radiotracer 18F-Fluoromisonidazole (FMISO) has been widely employed to image tumour hypoxia and is of interest to help develop novel hypoxia modifiers and guide radiation treatment planning. Yet, the optimal post-injection (p.i.) timing of hypoxic imaging remains questionable. Therefore, we investigated the correlation between hypoxia-related quantitative values in FMISO-PET acquired at 2 and 4 h p.i. in patients with non-small cell lung cancer (NSCLC). Patients with resectable NSCLC participated in the ATOM clinical trial (NCT02628080) which investigated the hypoxia modifying effects of atovaquone. Two-hour and four-hour FMISO PET/CT images acquired at baseline and pre-surgery visits (n = 58) were compared. Cohort 1 (n = 14) received atovaquone treatment, while cohort 2 (n = 15) did not. Spearman's rank correlation coefficients (ρ) assessed the relationship between hypoxia-related metrics, including standardised uptake value (SUV), tumour-to-blood ratio (TBR), and tumour hypoxic volume (HV) defined by voxels with TBR ≥ 1.4. As the primary imaging-related trial endpoint used to evaluate the action of atovaquone on tumour hypoxia in patients with NSCLC was change in tumour HV from baseline, this was also assessed in patients (n = 20) with sufficient baseline 2- and 4-h scan HV to reliably measure change (predefined as ≥ 1.5 mL). Tumours were divided into four subregions or distance categories: edge, outer, inner, and centre, using MATLAB. In tumours overall, strong correlation (P < 0.001) was observed for SUV ρ = 0.87, SUV ρ = 0.91, TBR ρ = 0.83 and TBR ρ = 0.81 between 2- and 4-h scans. Tumour HV was moderately correlated (P < 0.001) with ρ = 0.69 between 2- and 4-h scans. Yet, in tumour subregions, the correlation of HV decreased from the centre ρ = 0.71 to the edge ρ = 0.45 (P < 0.001). SUV, TBR, and HV values were consistently higher on 4-h scans than on 2-h scans, indicating better tracer-to-background contrast. For instance, for TBR, the mean, median, and interquartile range were 1.9, 1.7, and 1.6-2.0 2-h p.i., and 2.6, 2.4, and 2.0-3.0 4-h p.i., respectively. Our results support that FMISO-PET scans should be performed at 4 h p.i. to evaluate tumour hypoxia in NSCLC.Trial registration: ClinicalTrials.gov, NCT02628080. Registered 11/12/2015, https://clinicaltrials.gov/ct2/show/NCT02628080 .
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Positron Emission Tomography Computed Tomography; Atovaquone; Radiopharmaceuticals; Lung Neoplasms; Misonidazole; Positron-Emission Tomography; Hypoxia; Cell Hypoxia
PubMed: 36526815
DOI: 10.1038/s41598-022-26199-7 -
Frontiers in Oncology 2022Glioblastomas (GBM) are the most common and aggressive form of primary malignant brain tumor in the adult population, and, despite modern therapies, patients often...
Glioblastomas (GBM) are the most common and aggressive form of primary malignant brain tumor in the adult population, and, despite modern therapies, patients often develop recurrent disease, and the disease remains incurable with median survival below 2 years. Resistance to bevacizumab is driven by hypoxia in the tumor and evofosfamide is a hypoxia-activated prodrug, which we tested in a phase 2, dual center (University of Texas Health Science Center in San Antonio and Dana Farber Cancer Institute) clinical trial after bevacizumab failure. Tumor hypoxic volume was quantified by 18F-misonidazole PET. To identify circulating metabolic biomarkers of tumor hypoxia in patients, we used a high-resolution liquid chromatography-mass spectrometry-based approach to profile blood metabolites and their specific enantiomeric forms using untargeted approaches. Moreover, to evaluate early response to treatment, we characterized changes in circulating metabolite levels during treatment with combined bevacizumab and evofosfamide in recurrent GBM after bevacizumab failure. Gamma aminobutyric acid, and glutamic acid as well as its enantiomeric form D-glutamic acid all inversely correlated with tumor hypoxia. Intermediates of the serine synthesis pathway, which is known to be modulated by hypoxia, also correlated with tumor hypoxia (phosphoserine and serine). Moreover, following treatment, lactic acid was modulated by treatment, likely in response to a hypoxia mediated modulation of oxidative vs glycolytic metabolism. In summary, although our results require further validation in larger patients' cohorts, we have identified candidate metabolic biomarkers that could evaluate the extent of tumor hypoxia and predict the benefit of combined bevacizumab and evofosfamide treatment in GBM following bevacizumab failure.
PubMed: 36226069
DOI: 10.3389/fonc.2022.900082 -
Medicine Jul 2022Generated 18F-fluoromisonidazole (18F-FMISO) positron emission tomography (PET) images for glioblastoma are highly sought after because 18F-FMISO can be radioactive, and...
Generated 18F-fluoromisonidazole (18F-FMISO) positron emission tomography (PET) images for glioblastoma are highly sought after because 18F-FMISO can be radioactive, and the imaging procedure is not easy. This study aimed to explore the feasibility of using advanced magnetic resonance (MR) images to generate regional 18F-FMISO PET images and its predictive value for survival. Twelve kinds of advanced MR images of 28 patients from The Cancer Imaging Archive were processed. Voxel-by-voxel correlation analysis between 18F-FMISO images and advanced MR images was performed to select the MR images for generating regional 18F-FMISO images. Neural network algorithms provided by the MATLAB toolbox were used to generate regional 18F-FMISO images. The mean square error (MSE) was used to evaluate the regression effect. The prognostic value of generated 18F-FMISO images was evaluated by the Mantel-Cox test. A total of 299 831 voxels were extracted from the segmented regions of all patients. Eleven kinds of advanced MR images were selected to generate 18F-FMISO images. The best neural network algorithm was Bayesian regularization. The MSEs of the training, validation, and testing groups were 2.92E-2, 2.9E-2, and 2.92E-2, respectively. Both the maximum Tissue/Blood ratio (P = .017) and hypoxic volume (P = .023) of the generated images were predictive factors of overall survival, but only hypoxic volume (P = .029) was a predictive factor of progression-free survival. Multiple advanced MR images are feasible to generate qualified regional 18F-FMISO PET images using neural networks. The generated images also have predictive value in the prognostic evaluation of glioblastoma.
Topics: Bayes Theorem; Glioblastoma; Humans; Misonidazole; Neural Networks, Computer; Positron-Emission Tomography; Radiopharmaceuticals; Tomography, X-Ray Computed
PubMed: 35905276
DOI: 10.1097/MD.0000000000029572 -
European Journal of Nuclear Medicine... Oct 2022To identify the optimal threshold in F-fluoromisonidazole (FMISO) PET images to accurately locate tumor hypoxia by using electron paramagnetic resonance imaging (pO...
The optimal F-fluoromisonidazole PET threshold to define tumor hypoxia in preclinical squamous cell carcinomas using pO electron paramagnetic resonance imaging as reference truth.
PURPOSE
To identify the optimal threshold in F-fluoromisonidazole (FMISO) PET images to accurately locate tumor hypoxia by using electron paramagnetic resonance imaging (pO EPRI) as ground truth for hypoxia, defined by pO [Formula: see text] 10 mmHg.
METHODS
Tumor hypoxia images in mouse models of SCCVII squamous cell carcinoma (n = 16) were acquired in a hybrid PET/EPRI imaging system 2 h post-injection of FMISO. T2-weighted MRI was used to delineate tumor and muscle tissue. Dynamic contrast enhanced (DCE) MRI parametric images of K and v were generated to model tumor vascular properties. Images from PET/EPR/MRI were co-registered and resampled to isotropic 0.5 mm voxel resolution for analysis. PET images were converted to standardized uptake value (SUV) and tumor-to-muscle ratio (TMR) units. FMISO uptake thresholds were evaluated using receiver operating characteristic (ROC) curve analysis to find the optimal FMISO threshold and unit with maximum overall hypoxia similarity (OHS) with pO EPRI, where OHS = 1 shows perfect overlap and OHS = 0 shows no overlap. The means of dice similarity coefficient, normalized Hausdorff distance, and accuracy were used to define the OHS. Monotonic relationships between EPRI/PET/DCE-MRI were evaluated with the Spearman correlation coefficient ([Formula: see text]) to quantify association of vasculature on hypoxia imaged with both FMISO PET and pO EPRI.
RESULTS
FMISO PET thresholds to define hypoxia with maximum OHS (both OHS = 0.728 [Formula: see text] 0.2) were SUV [Formula: see text] 1.4 [Formula: see text] SUV and SUV [Formula: see text] 0.6 [Formula: see text] SUV. Weak-to-moderate correlations (|[Formula: see text]|< 0.70) were observed between PET/EPRI hypoxia images with vascular permeability (K) or fractional extracellular-extravascular space (v) from DCE-MRI.
CONCLUSION
This is the first in vivo comparison of FMISO uptake with pO EPRI to identify the optimal FMISO threshold to define tumor hypoxia, which may successfully direct hypoxic tumor boosts in patients, thereby enhancing tumor control.
Topics: Animals; Carcinoma, Squamous Cell; Cell Hypoxia; Electron Spin Resonance Spectroscopy; Hypoxia; Mice; Misonidazole; Positron-Emission Tomography; Radiopharmaceuticals; Tomography, X-Ray Computed; Tumor Hypoxia
PubMed: 35792927
DOI: 10.1007/s00259-022-05889-4 -
Radiology. Imaging Cancer May 2022Purpose To determine the variance and correlation with tumor viability of fluorine 18 (F) fluoromisonidazole (FMISO) uptake in hepatocellular carcinoma (HCC) prior to...
Limitations of Fluorine 18 Fluoromisonidazole in Assessing Treatment-induced Tissue Hypoxia after Transcatheter Arterial Embolization of Hepatocellular Carcinoma: A Prospective Pilot Study.
Purpose To determine the variance and correlation with tumor viability of fluorine 18 (F) fluoromisonidazole (FMISO) uptake in hepatocellular carcinoma (HCC) prior to and after embolization treatment. Materials and Methods In this single-arm, single-center, prospective pilot study between September 2016 and March 2017, participants with at least one tumor measuring 1.5 cm or larger with imaging or histologic findings diagnostic for HCC were enrolled (five men; mean age, 68 years; age range, 61-76 years). Participants underwent F-FMISO PET/CT before and after bland embolization of HCC. A tumor-to-liver ratio (TLR) was calculated by using standardized uptake values of tumor and liver. The difference in mean TLR before and after treatment was compared by using a Wilcoxon rank sum test, and correlation between TLR and tumor viability was assessed by using the Spearman rank correlation coefficient. Results Four participants with five tumors were included in the final analysis. The median tumor diameter was 3.2 cm (IQR, 3.0-3.9 cm). The median TLR before treatment was 0.97 (IQR, 0.88-0.98), with a variance of 0.02, and the median TLR after treatment was 0.85 (IQR, 0.79-1), with a variance of 0.01; both findings indicate a narrow range of F-FMISO uptake in HCC. The Spearman rank correlation coefficient was 0.87, indicating a high correlation between change in TLR and nonviable tumor. Conclusion Although there was a correlation between change in TLR and response to treatment, the low signal-to-noise ratio of F-FMISO in the liver limited its use in HCC. Molecular Imaging-Clinical Translation, Embolization, Abdomen/Gastrointestinal, Liver Clinical trial registration no. NCT02695628 © RSNA, 2022.
Topics: Aged; Carcinoma, Hepatocellular; Embolization, Therapeutic; Fluorine; Humans; Hypoxia; Liver Neoplasms; Male; Middle Aged; Misonidazole; Pilot Projects; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals
PubMed: 35485937
DOI: 10.1148/rycan.210094 -
Radiotherapy and Oncology : Journal of... Jun 2022Tumor hypoxia is a major cause of resistance to radiochemotherapy in locally advanced head-and-neck cancer (LASCCHN). We present results of a randomized phase II trial... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND PURPOSE
Tumor hypoxia is a major cause of resistance to radiochemotherapy in locally advanced head-and-neck cancer (LASCCHN). We present results of a randomized phase II trial on hypoxia dose escalation (DE) in LASCCHN based on dynamic [F]FMISO (dynFMISO) positron emission tomography (PET). The purpose was to confirm the prognostic value of hypoxia PET and assess feasibility, toxicity and efficacy of hypoxia-DE.
MATERIALS AND METHODS
Patients with LASCCHN underwent baseline dynFMISO PET/CT. Hypoxic volumes (HV) were derived from dynFMISO data. Patients with hypoxic tumors (HV > 0) were randomized into standard radiotherapy (ST: 70Gy/35fx) or dose escalation (DE: 77Gy/35fx) to the HV. Patients with non-hypoxic tumors were treated with ST. After a minimum follow-up of 2 years feasibility, acute/late toxicity and local control (LC) were analyzed.
RESULTS
The study was closed prematurely due to slow accrual. Between 2009 and 2017, 53 patients were enrolled, 39 (74%) had hypoxic tumors and were randomized into ST or DE. For non-hypoxic patients, 100% 5-year LC was observed compared to 74% in patients with hypoxic tumors (p = 0.039). The difference in 5-year LC between DE (16/19) and ST (10/17) was 25%, p = 0.150. No relevant differences related to acute and late toxicities between the groups were observed.
CONCLUSION
This study confirmed the prognostic value of hypoxia PET in LASCCHN for LC. Outcome after hypoxia DE appears promising and may support the concept of DE. Slow accrual and premature closure may partly be due to a high complexity of the study setup which needs to be considered for future multicenter trials.
Topics: Head and Neck Neoplasms; Humans; Hypoxia; Misonidazole; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Radiopharmaceuticals
PubMed: 35395276
DOI: 10.1016/j.radonc.2022.03.021 -
European Journal of Nuclear Medicine... Apr 2022Intratumoral hypoxia increases resistance of head-and-neck squamous cell carcinoma (HNSCC) to radiotherapy. [F]FMISO PET imaging enables noninvasive hypoxia monitoring,... (Clinical Trial)
Clinical Trial
Interleukin-6 as surrogate marker for imaging-based hypoxia dynamics in patients with head-and-neck cancers undergoing definitive chemoradiation-results from a prospective pilot trial.
PURPOSE
Intratumoral hypoxia increases resistance of head-and-neck squamous cell carcinoma (HNSCC) to radiotherapy. [F]FMISO PET imaging enables noninvasive hypoxia monitoring, though requiring complex logistical efforts. We investigated the role of plasma interleukin-6 (IL-6) as potential surrogate parameter for intratumoral hypoxia in HNSCC using [F]FMISO PET/CT as reference.
METHODS
Within a prospective trial, serial blood samples of 27 HNSCC patients undergoing definitive chemoradiation were collected to analyze plasma IL-6 levels. Intratumoral hypoxia was assessed in treatment weeks 0, 2, and 5 using [F]FMISO PET/CT imaging. The association between PET-based hypoxia and IL-6 was examined using Pearson's correlation and multiple regression analyses, and the diagnostic power of IL-6 for tumor hypoxia response prediction was determined with receiver-operating characteristic analyses.
RESULTS
Mean IL-6 concentrations were 15.1, 19.6, and 31.0 pg/mL at baseline, week 2 and week 5, respectively. Smoking (p=0.050) and reduced performance status (p=0.011) resulted in higher IL-6 levels, whereas tumor (p=0.427) and nodal stages (p=0.334), tumor localization (p=0.439), and HPV status (p=0.294) had no influence. IL-6 levels strongly correlated with the intratumoral hypoxic subvolume during treatment (baseline: r=0.775, p<0.001; week 2: r=0.553, p=0.007; week 5: r=0.734, p<0.001). IL-6 levels in week 2 were higher in patients with absent early tumor hypoxia response (p=0.016) and predicted early hypoxia response (AUC=0.822, p=0.031). Increased IL-6 levels at week 5 resulted in a trend towards reduced progression-free survival (p=0.078) and overall survival (p=0.013).
CONCLUSION
Plasma IL-6 is a promising surrogate marker for tumor hypoxia dynamics in HNSCC patients and may facilitate hypoxia-directed personalized radiotherapy concepts.
TRIAL REGISTRATION
The prospective trial was registered in the German Clinical Trial Register (DRKS00003830). Registered 20 August 2015.
Topics: Biomarkers; Cell Hypoxia; Head and Neck Neoplasms; Humans; Hypoxia; Interleukin-6; Misonidazole; Pilot Projects; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals; Squamous Cell Carcinoma of Head and Neck
PubMed: 34773163
DOI: 10.1007/s00259-021-05602-x